This invention relates to neurological disorders and neurodegenerative syndromes with an autoimmune component. More particularly, this invention relates to compositions and methods for diagnosis and treatment of neurological disorders and neurodegenerative syndromes wherein autoantibodies to one or more neuronal glutamate receptor subunits are associated with the disorders and syndromes.
Neurological disorders and neurodegenerative syndromes afflict an alarming number of individuals and present an increasing economic challenge to the health care system since little is known regarding their causes, their diagnosis is often subjective, and many lack effective treatment. Mental activity is ultimately determined by the capacity of neurons to communicate at synapses. The location of neurotransmitter receptors at synapses makes them a likely target for alterations during aging and in diseases that alter behavior and cognition. Among these many receptor types are the neuronal glutamate receptors (GluR's), .gamma.-aminobutyric acid receptors (GABAR's), nicotinic acetylcholine receptors, serotonin receptors, dopamine receptors, and the like.
GluR's comprise the predominant fast excitatory neurotransmitter system in the mammalian central nervous system and could play a role in the etiology of some forms of disease thereof. D. Choi, 23 J. Neurobiol. 1261 (1992). For example, excessive glutamate receptor stimulation has been linked to subsequent neuronal death. This excitotoxicity is thought to play a role in nervous system destruction after stroke, trauma, epilepsy, Alzheimer's disease, and Huntington's disease.
Similar to other ligand-activated ion channels, there are numerous subunits that compose the glutamate receptor family. The number of native GluR's is unknown, and the potential diversity of these receptors is immense. Sixteen subunits of the glutamate receptor have been molecularly cloned to date. M. Hollmann & S. F. Heinemann, Cloned Glutamate Receptors, 17 Ann. Rev. Neurosci. 31-108 (1993). Currently, these subunits are broadly grouped on the basis of sequence identity and response to agonists when expressed as a receptor in Xenopus oocytes or in transfected cells. These divisions include cDNAs that encode receptors with N-methyl-D-aspartate (NMDA) pharmacology and at least 9 cDNAs that encode non-NMDA receptor types. This latter group can be subdivided into three groups based upon similarity of primary sequence and/or function. GluR1, GluR2, GluR3, and GluR4 form receptors that are responsive to kainic acid and .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and bind AMPA with high affinity. GluR5, GluR6, and GluR7 form receptors that are responsive to kainic acid or bind kainic acid with high affinity. KA1 and KA2 do not function alone, but form high affinity kainic acid binding sites or kainate/AMPA responsive receptors when expressed with other GluR subunits in cultured cells.
Rasmussen's encechalitis is a childhood disease of intractable focal seizures and characteristic inflammatory histoathology in the affected brain hemisphere. Two rabbits injected with a bacterial fusion protein expressing a portion of a glutamate receotor subunit, GluR3, were observed to develop seizures and early histopathological changes similar to those observed in Rasmussen's encephalitis. To test the hypothesis that an autoimmune response to GluR3 is associated with Rasmussen's encephalitis, sera from affected patients and age and sex matched controls were examined for immunoreactivity to GluR subunits using immunoblot analysis and transfected cells expressing GluR3. Rasmussen patients with active disease were found to have circulating IgG antibodies to GluR3. In a therapeutic trial of one patient, removal of circulating GluR3 antibodies by plasmapheresis correlated with a reduced rate of seizure and improved cognitive function. S. Rogers et al., Autoantibodies to Glutamate Receptor GluR3 in Rasmussen's Encephalitis, 265 Science 648 (1994); U.S. patent application Ser. No. 08/109,234.
Although thought to play a role in neurological disease, the mechanism underlying the role of such receptors is obscure. The majority of current research seeks to identify drugs that act upon these receptors directly or that modify cellular processes in the brain to maintain the correct expression of these receptors.
In view of the foregoing, it will be appreciated that compositions and methods for screening and treating neurological disorders and neurodegenerative syndromes would be significant advancements in the art.